The present invention provides a pharmaceutical composition which is effective for eradication Helicobacter pylori living in human stomach and, accordingly, said invention is utilized in the medical field.
The present invention also provides a complex of 4-[4-(4-methylbenzyloxycarbonyl)phenyl]phenyl trans-4-guanidinomethylcyclohexanecarboxylate or an acid addition salt thereof with xcex2-cyclodextrin.
Helicobacter pylori is a bacterium which has recently attached considerable attention in view of its relationship with diseases of digestive organs. It has become an important factor to be taken into consideration especially when diseases, particularly ulcer, of stomach and duodenum is investigated.
As the drugs effective for inhibiting the growth of Helicobacter pylori antibiotic substances such as ampicillin, amoxicillin, caphalexin and clarithromycin and synthetic antibacterials such as ofloxacin and ciprofloxacin have been known. It has been clarified that Helicobacter pylori has participated in recurrence of ulcer and, at the same time, prevention of recurrence of ulcer by a combined use of those antibacterials with antiulcer agent has been investigated.
Incidentally, when anitiobiotics or synthetic antibacterials are administered, they are absorbed from digestive organs into blood and arrive at the diseased site to achieve the effect while some of them are excreted after passing through the digestive organs and, when the drug passes through the intestinal tract, many bacteria living in intestine are killed whereby enterobacterial fleora is unbalanced. Accordingly, administration of such a drug for long term is to be avoided.
Since Helicobacter pylori is a bacterium living in stomach, there has been a demand for a compound having a property that its activity to said bacterium is effectively achieved in stomach and, after that, the antibacterial activity decreases when it moves to duodenum and then to small intestine and finally said activity disappears. Incidentally, there is a compound whose generic name is benexate hydrochloride and it has been known that said compound has an anti-Helicobacter pylori activity with MICs ranging from 25 to 50 xcexcg/ml (xe2x80x9cDiseases of Digestive Organs and Helicobacter pylorixe2x80x9d, page 91; published by Medical Review).
The present applicant previously found a compound showing an effective antibacterial activity which is specific to Helicobacter pylori although it was a result of the test in vitro (WO 96/06825) and, in view of the fact that the result in vivo does not always coincide with that in vitro. The mode of its use was investigated whereby the present invention has been achieved.
The present invention is to provide a composition of 4-[4-(4-methylbenzyloxycarbonyl)phenyl]phenyl trans-4-guanidinomethylcyclohexanecarboxylate or an acid addition salt thereof (hereinafter, it will be referred to as xe2x80x9cthe present compoundxe2x80x9d) which is suitable for exterminating or eradicating Helicobacter pylori in living body by the use of the present compound.
It has been known that, although the present compound exhibits an antibacterial action quite specifically to Helicobacter pylori according to an in vitro test (WO 96/06825), such an antibacterial activity in vitro is not available in an in vivo test as it is. As one of the causes, we took the solubility of the present compound into consideration but, after various investigations, it has been found that an improvement in solubility only is not able to afford the effect of eradication or extermination of Helicobacter pylori and, at the same time, we have found that a combined use of the present compound with cyclodextrin, particularly with xcex2-cyclodextrin, is effective in eradication or extermination of Helicobacter pylori in living body whereupon the present invention has been achieved.
The present invention provides a pharmaceutical composition having an anti-Helicobacter pylori action which contains 4-[4-(4-methylbenzyloxycarbonyl)phenyl]phenyl trans-4-guanidinomethylcyclohexanecarboxylate or an acid addition salt thereof and xcex2-cyclodextrin.
The present invention also provides a complex of 4-[4- (4-methyl-benzyloxycarbonyl)phenyl]phenyl trans-4-guanidinomethylcyclohexanecarboxylate or an acid addition salt thereof with xcex2-cyclodextrin.
The composite which is an object of the present invention is also an effective component of the pharmaceutical composition of the present invention and it consists of the present compound and xcex2-cyclodextrin and may be prepared by grinding the two substances or by making them an aqueous solution followed by subjecting to a treatment of spray-drying, freeze-drying or drying by means of concentration.
Further, even In the case where they are just mixed, it is effective in eradication or extermination of Helicobacter pylori which is an object of the present invention provided that said mixture is dissolved in water. Therefore, such a mixture is covered by the present invention as well.
Accordingly, the present invention provides a mixture or a complex (inclusion compound) of 4-[4-(4-methylbenzyloxycarbonyl)phenyl]phenyl trans-4-guanidinomethylcyclohexane carboxylate or an acid addition salt thereof and xcex2-cyclodextrin and also offers a composition containing the same which has an anti-Helicobacter pylori action.